Process for preparing substituted phenylisoxazoline derivatives

ABSTRACT

The present invention relates to a process for preparing substituted phenylisoxazoline derivatives.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is Divisional Application of U.S. patent applicationSer. No. 15/548,216, filed Aug. 2, 2017, which is a § 371 National StageApplication of PCT/EP2016/054192, filed Feb. 29, 2016, which claimspriority to European Application No. 15157803.6 filed Mar. 5, 2015. Eachof these applications is incorporated by reference in its entirety.

BACKGROUND Field of the Invention

The present invention relates to a process for preparing substitutedphenylisoxazoline derivatives.

Description of Related Art

Substituted phenylisoxazoline derivatives are useful intermediates inthe production of active agrochemical ingredients (see, for example, WO2008/013925, WO 2009/094407, WO 2010/123791).

There are various known processes for preparing such substitutedphenylisoxazoline derivatives.

WO 2011/085170 describes, for example, a process for preparing thesephenylisoxazoline derivatives by [3+2] cycloaddition with a chloroximewith a styrene and downstream Grignard addition and halogenation (Scheme1).

A disadvantage of this process is that the use of further functionalgroups which can react directly with a Grignard reagent is impossible.

WO 2011/085170 describes, for example, a process for preparing thesephenylisoxazoline derivatives by [3+2] cycloaddition with a chloroximewith a styrene and downstream halogenation (Scheme 2).

Disadvantages of this process are the technically complex preparation ofthe chloroxime shown.

WO 2011/072207 describes a [3+2] cycloaddition proceeding from a styrenewith a chloroxime containing the required haloketone (Scheme 3).

Disadvantages of this process are the technically difficult preparationof the chloroxime shown and the large excesses required.

WO 2008/013925 describes the reaction of dichloroacetone with tert-butylnitrite and the subsequent [3+2] cycloaddition with a styrene (Scheme4).

A disadvantage of this process is that dichloroacetone is not availablein industrial volumes and the reaction with tert-butyl nitrite isdemanding for safety reasons.

Because of the importance of substituted phenylisoxazoline derivativesas a unit for synthesis of novel active agrochemical ingredients, theproblem addressed is that of finding a process which can be used on theindustrial scale and inexpensively. It is also desirable to obtain thespecific phenylisoxazoline derivatives with high yield and high purity,such that the target compound preferably does not have to be subjectedto any further potentially complex purification.

SUMMARY

This problem was solved by a process for preparing substitutedphenylisoxazoline derivatives of the formula (I):

in which

R¹ is methyl, bromomethyl or chloromethyl;

R² is halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl and

R³ is C₁-C₄-alkylsulphonyloxy, C₁-C₄-haloalkylsulphonyloxy,

characterized in that, in step (i), a chloroxime of the formula (II)

in which R⁴ is C₁-C₁₂-alkyl,

is reacted with a styrene of the formula (III)

in which R² and R³ are as defined above,

in the presence of an inorganic base in an organic aprotic solvent togive the corresponding phenylisoxazoline of the formula (IV)

in which R², R³ and R⁴ are as defined above,

and the latter then reacts, in step (ii), with an organometallic reagentand an organic base in an organic aprotic solvent to give the ketone ofthe formula (Ia)

in which R² and R³ are as defined above,

and then, in step (iii), in the presence of a halogenating agent in asolvent, the haloketone of the formula (Ib) is formed

in which R² and R³ are as defined above and

X is chlorine or bromine.

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

Preference is given to a process according to the invention in which theradical definitions of the formulae (I), (Ia), (Ib), (II), (III) and(IV) are as follows:

R¹ is methyl, bromomethyl, chloromethyl;

R² is chlorine or bromine;

R³ is methylsulphonyloxy or ethylsulphonyloxy;

R⁴ is C₁-C₄-alkyl and

X is chlorine or bromine.

Particular preference is given to a process according to the inventionin which the radical definitions of the formulae (I), (Ia), (Ib), (II),(III) and (IV) are as follows:

R¹ is methyl, bromomethyl;

R² is chlorine;

R³ is methylsulphonyloxy;

R⁴ is methyl, ethyl and

X is bromine.

A further aspect of the present invention is compounds of the formula(IV):

in which

R² is halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl;

R³ is C₁-C₄-alkylsulphonyloxy, C₁-C₄-haloalkylsulphonyloxy and

R⁴ is C₁-C₁₂-alkyl.

Preference is given to compounds of the formula (IV)

in which

R² is chlorine or bromine;

R³ is methylsulphonyloxy or ethylsulphonyloxy and

R⁴ is C₁-C₄-alkyl.

Particular preference is given to compounds of the formula (IV)

in which

R² is chlorine;

R³ is methylsulphonyloxy and

R⁴ is methyl, ethyl.

A further aspect of the present invention is compounds of the formula(Ia):

in which

R² is halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl and

R³ is C₁-C₄-alkylsulphonyloxy, C₁-C₄-haloalkylsulphonyloxy.

Preference is given to compounds of the formula (Ia)

in which

R² is chlorine or bromine and

R³ is methylsulphonyloxy or ethylsulphonyloxy.

Particular preference is given to compounds of the formula (Ia)

in which

R² is chlorine and

R³ is methylsulphonyloxy.

A further aspect of the present invention is compounds of the formula(Ib):

in which

R² is halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl;

R³ is C₁-C₄-alkylsulphonyloxy, C₁-C₄-haloalkylsulphonyloxy and

X is chlorine or bromine.

Preference is given to compounds of the formula (Ib)

in which

R² is chlorine or bromine;

R³ is methylsulphonyloxy or ethylsulphonyloxy and

X is chlorine or bromine.

Particular preference is given to compounds of the formula (Ib)

in which

R² is chlorine;

R³ is methylsulphonyloxy and

X is bromine.

General Definitions

In the definitions of the symbols given in the above formulae,collective terms which are generally representative of the followingsubstituents were used:

Halogen: fluorine, chlorine, bromine and iodine;

Alkyl: saturated straight-chain or branched hydrocarbyl radicals having1 to 12 carbon atoms, for example (but not limited to) C₁-C₆-alkyl suchas methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and1-ethyl-2-methylpropyl;

Alkylsulphonyl: saturated, straight-chain or branched alkylsulphonylradicals having 1 to 4 carbon atoms, for example (but not limited to)C₁-C₆-alkylsulphonyl such as methylsulphonyl, ethylsulphonyl,propylsulphonyl, 1-methylethylsulphonyl, butylsulphonyl,1-methylpropylsulphonyl, 2-methylpropylsulphonyl,1,1-dimethylethylsulphonyl;

Haloalkyl: straight-chain or branched alkyl groups having 1 to 4 carbonatoms (as specified above), where some or all of the hydrogen atoms inthese groups may be replaced by halogen atoms as specified above, forexample chloromethyl, bromomethyl, dichloromethyl, trichloromethyl,fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl,dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl,1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl,2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and1,1,1-trifluoroprop-2-yl;

Alkoxy: saturated straight-chain or branched alkoxy radicals having 1 to4 carbon atoms, for example (but not limited to) methoxy, ethoxy,propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy,1,1-dimethylethoxy. This definition also applies to alkoxy as part of acomposite substituent, for example haloalkoxy, alkynylalkoxy etc.,unless defined elsewhere.

Description of the Process

The reaction according to the invention is shown in Scheme 5.

The desired phenylisoxazoline derivatives of the general formula (I) areobtained with good yields and in high purity by the process according tothe invention.

The process according to the invention has the advantage over theprocesses described above that the starting materials are preparable onthe industrial scale and the process is surprisingly compatible withbase-labile alkylsulphonyloxy and haloalkylsulphonyloxy groups.

The application accordingly relates to a process for preparingparticular phenylisoxazoline derivatives of the general formula (II),comprising the following steps:

Step (i):

Reacting the chloroxime of the formula (II) with a styrene of theformula (III) in the presence of an organic base and an organic aproticsolvent to give the corresponding isoxazoline of the formula (IV).

Useful solvents for the process according to the invention are inprinciple any organic aprotic solvents or solvent mixtures that areinert under the reaction conditions, including ketones, for exampleacetone, diethyl ketone, methyl ethyl ketone and methyl isobutyl ketone;nitriles, for example acetonitrile and butyronitrile; ethers, forexample dimethoxyethane (DME), tetrahydrofuran (THF), 2-methyl-THF and1,4-dioxane; hydrocarbons and halogenated hydrocarbons such as hexane,heptane, cyclohexane, methylcyclohexane, toluene, ortho-xylene,meta-xylene, para-xylene, mesitylene, chlorobenzene,ortho-dichlorobenzene or nitrobenzene; esters, for example methylacetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butylacetate, isobutyl acetate, sec-butyl acetate, hexyl acetate, cyclohexylacetate, 2-ethylhexyl acetate. Preferably, the solvent is selected fromthe group of the esters: methyl acetate, ethyl acetate, n-propylacetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butylacetate, hexyl acetate, cyclohexyl acetate, 2-ethylhexyl acetate ormixtures of these solvents or of the nitriles: acetonitrile,butyronitrile. More preferably, ethyl acetate and isobutyl acetate areused.

Suitable inorganic bases include carbonates (for example lithiumcarbonate, sodium carbonate, sodium hydrogencarbonate, potassiumcarbonate and calcium carbonate), phosphates (for example potassiumphosphate, sodium phosphate and lithium phosphate) and hydroxides (forexample potassium hydroxide, sodium hydroxide and lithium hydroxide).Preferably, Na₂CO₃ and NaHCO₃ are used.

The temperature in the process according to the invention can be variedwithin wide limits. A customary operating temperature is from −10° C. to60° C., preferably from 5° C. to 50° C. More preferably, the reaction isconducted at a temperature in the range from 10° C. to 40° C.

The process according to the invention is typically conducted atstandard pressure. It is also possible to conduct the reaction underreduced pressure or under elevated pressure.

The molar ratios of the compound of the formula (II) to the compound ofthe formula (III) and to the inorganic base may vary within wide ranges.They are generally not subject to any restriction.

In step (i), it is advantageous when the molar ratio of the compound ofthe formula (II) to the compound of the formula (III) is in the rangefrom 0.9 to 3.0, preferably in the range from 1.0 to 2.0. Morepreferably, the molar ratio is in the range from about 1.0 to 1.5. It ispreferable that the molar ratio of the compound of the formula (II) tothe inorganic base is in the range from 0.1 to 1.0, more preferably inthe range from 0.2 to 1.0. More preferably, the molar ratio is in therange from 0.25 to 1.0.

The chloroximes of the formula (II) are known from the literature andsome are available in industrial volumes (see, for example, TetrahedronLetters 2011, Volume 52, Issue 43, 5656-5658).

The styrenes of the formula (III) can be prepared by general synthesismethods; see, for example, Organic Synthesis 1928, 8, 84; OrganicSynthesis 1948, 28, 31; Organic Synthesis 1953, 33, 62; OrganicSynthesis 1966, 46, 89; Organic Synthesis 2006, 83, 45.

The reaction time is short and is in the range from 0.5 to 5 hours. Alonger reaction time is possible, but is not economically worthwhile.

Step (ii):

Reacting the phenylisoxazoline of the formula (IV) with anorganometallic reagent and an organic base in an organic aprotic solventto give the ketone of the formula (Ia).

Useful solvents for the process according to the invention in principleinclude any organic aprotic solvents or solvent mixtures that are inertunder the reaction conditions, including: ethers, for exampledimethoxyethane (DME), tetrahydrofuran (THF), 2-methyl-THF and1,4-dioxane; hydrocarbons and halogenated hydrocarbons such as hexane,heptane, cyclohexane, methylcyclohexane, toluene, ortho-xylene,meta-xylene, para-xylene, mesitylene, chlorobenzene orortho-dichlorobenzene. Preference is given to using tetrahydrofuran(THF) or 2-methyl-THF.

Examples of useful organic bases for the process according to theinvention include the following: triethylamine, diethyl-iso-propylamine,tri-n-butylamine, pyridine, picoline, lutidine and collidine. Preferenceis given to using triethylamine

Useful organometallic reagents for the process according to theinvention include: methyllithium, methylmagnesium iodide,methylmagnesium bromide and methylmagnesium chloride. Preference isgiven to the use of methylmagnesium bromide and methylmagnesiumchloride.

The temperature in the process according to the invention can be variedwithin wide limits. A customary operating temperature is from −10° C. to20° C. Preferably, the reaction is conducted at a temperature in therange from −5° C. to 20° C.

The process according to the invention is typically conducted atstandard pressure. It is also possible to conduct the reaction underreduced pressure or under elevated pressure.

In step (ii) of the process according to the invention, the molar ratiosof the compound of the formula (IV) to the organometallic reagent and tothe organic base may vary within wide ranges. They are generally notsubject to any restriction.

In step (ii), it is preferable when the molar ratio of theorganometallic reagent to the compound of the formula (IV) is in therange from 1.0 to 3.0, more preferably in the range from 1.2 to 2.5.Most preferably, the molar ratio is in the range from 1.5 to 2.3. It isadditionally preferable when the ratio of the organometallic reagent tothe organic base is in the range from 0.8 to 1.5, more preferably in therange from 0.9 to 1.1.

The reaction time is short and is in the range from about 0.5 to about 5hours. A longer reaction time is possible, but is not economicallyworthwhile.

The transformation of esters to ketones using a Grignard reagent with anorganic base is known from the literature (see, for example, Baraldi,Pier Giovani et al Tetrahedron 1987, 43(1), 235-42).

Step (iii):

Reacting the compound of the formula (Ia) with a halogenating agent in asolvent to give the haloketone (Ib).

Useful halogenating agents for the process according to the inventioninclude chlorine and bromine, preferably bromine.

Useful solvents for the process according to the invention include thefollowing solvents or solvent mixtures: nitriles, for exampleacetonitrile and butyronitrile; ethers, for example dimethoxyethane(DME), tetrahydrofuran (THF), 2-methyl-THF and 1,4-dioxane; hydrocarbonsand halogenated hydrocarbons such as hexane, heptane, cyclohexane,methylcyclohexane, toluene, ortho-xylene, meta-xylene, para-xylene,mesitylene, dichloromethane, chlorobenzene, ortho-dichlorobenzene ornitrobenzene; esters, for example methyl acetate, ethyl acetate,n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate,sec-butyl acetate, hexyl acetate, cyclohexyl acetate, 2-ethylhexylacetate, organic acids (for example acetic acid). Preferably,dichloromethane, acetic acid or dioxane is used, more preferably dioxaneor acetic acid.

The temperature in the process according to the invention can be variedwithin wide limits. A customary operating temperature is from 0° C. to120° C., preferably from 20° C. to 100° C., more preferably from 20° C.to 40° C.

The process according to the invention is typically conducted atstandard pressure. It is also possible to conduct the reaction underreduced pressure or under elevated pressure.

In step (iii) of the process according to the invention, the molarratios of the compound of the formula (Ia) to the halogenating agent mayvary within wide ranges. They are generally not subject to anyrestriction.

In step (iii), it is preferable when the molar ratio of compound of theformula (Ia) to the halogenating agent is in the range from 1.5 to 0.9,more preferably in the range from 1.3 to 1.1. Most preferably, the molarratio is in the range from 1.1 to 1.0.

The reaction time is short and is in the range from about 0.5 to about 5hours. A longer reaction time is possible, but is not economicallyworthwhile.

EXAMPLES

The present invention is elucidated in detail by the examples whichfollow, without restricting the invention to these examples.

Example 1 Ethyl5-{2-chloro-6-[(methylsulphonyl)oxy]phenyl}-4,5-dihydro-1,2-oxazole-3-carboxylate

To a mixture of 57.0 g (237 mmol) of 3-chloro-2-vinylphenylmethanesulphonate (content: 96.7%) in 50 ml of ethyl acetate are added54.4 g (355 mmol) of ethyl 2-chloro(hydroxyimino)acetate in 200 ml ofethyl acetate and 125 g (1.48 mol) of sodium hydrogencarbonate. Themixture is left to stir at 20-25° C. for 1.5 hours and then heated to40° C. for a further 2 hours. After cooling to room temperature, 500 mlof water are added and the lower, aqueous phase is removed. To theorganic phase are added 100 ml of a 1 N aqueous hydrochloric acid and100 ml of a saturated sodium chloride solution. The organic phase isfreed of the solvent on a rotary evaporator, and the residue iscrystallized from hexane and tert-butyl methyl ether. This affords 70.6g of ethyl5-{2-chloro-6-[(methylsulphonyl)oxy]phenyl}-4,5-dihydro-1,2-oxazole-3-carboxylatehaving a content of 99.2% in the form of a colourless solid (yield:85%).

¹H NMR (CD₃CN): 1.37 (t, 3 H), 3.35 (s, 3 H), 3.38 (dd, 1 H), 3.59 (dd,1 H), 4.31 (q, 2 H), 6.31 (dd, 1 H), 7.45-7.49 (m, 3 H) ppm.

Example 2 2-(3-Acetyl-4,5-dihydro-1,2-oxazol-5-yl)-3-chlorophenylmethanesulphonate

A solution of 100 g (279 mmol) of ethyl5-{2-chloro-6-[(methylsulphonyl)oxy]phenyl}-4,5-dihydro-1,2-oxazole-3-carboxylate(content: 97.0%) in 500 ml of methyl-THF is cooled to −5° C. and 62.1 g(614 mmol) of triethylamine are added. Subsequently, 200 ml (641 mmol)of methylmagnesium bromide (3.2 molar solution in methyl-THF) are addedat this temperature within 2 hours. The mixture is gradually added to600 ml of hydrochloric acid in ice-water. The mixture is extracted firstwith 500 ml of ethyl acetate and then with 200 ml of ethyl acetate. Thecombined organic phases are freed of the solvent on a rotary evaporatorand the residue is crystallized with 500 ml of heptane. This affords87.8 g of 2-(3-acetyl-4,5-dihydro-1,2-oxazol-5-yl)-3-chlorophenylmethanesulphonate having a content of 91.5% in the form of a colourlesssolid (yield: 91%).

¹H NMR [(D6)-DMSO]: 2.47 (s, 3 H), 3.20 (dd, 1 H), 3.52 (dd, 1 H), 3.53(s, 3 H), 6.26 (dd, 1 H), 7.50-7.58 (m, 3 H) ppm.

Example 3 2-[3-(Bromoacetyl)-4,5-dihydro-1,2-oxazol-5-yl]-3-chlorophenylmethanesulphonate

To a solution of 5.00 g (15.3 mmol) of2-(3-acetyl-4,5-dihydro-1,2-oxazol-5-yl)-3-chlorophenylmethanesulphonate (content: 97.3%) in 20 ml of dioxane are addeddropwise, at 20-25° C., 2.2 g (13.8 mmol) of bromine. After 2 hours, 10ml of water and 2×20 ml of dichloromethane are added. The combinedorganic phases are washed with 20 ml of sodium sulphite solution and theorganic phase is freed of the solvent on a rotary evaporator. Thisaffords 6.34 g of2-[3-(bromoacetyl)-4,5-dihydro-1,2-oxazol-5-yl]-3-chlorophenylmethanesulphonate having a content of 80.6% in the form of an orange oil(yield: 84%). The product is usable for the subsequent reactions withoutfurther purification.

¹H NMR (CD3CN): 3.33 (dd, 1 H), 3.35 (s, 3 H), 3.59 (dd, 1 H), 4.60 (s,2 H), 6.33 (dd, 1 H), 7.44-7.47 (m, 3 H) ppm.

1. Compound of formula (IV)

wherein R² is halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl; R³ isC₁-C₄-alkylsulphonyloxy, C₁-C₄-haloalkylsulphonyloxy and R⁴ isC₁-C₁₂-alkyl.
 2. Compound of formula (IV) according to claim 1, whereinR² is chlorine; R³ is methylsulphonyloxy and R⁴ is methyl, ethyl. 3.Compound of formula (Ia)

wherein R² is halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl and R³is C₁-C₄-alkylsulphonyloxy, C₁-C₄-haloalkylsulphonyloxy.
 4. Compound offormula (Ia) according to claim 3, wherein R² is chlorine and R³ ismethylsulphonyloxy.
 5. Compound of formula (Ib):

wherein R² is halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyl; R³ isC₁-C₄-alkylsulphonyloxy, C₁-C₄-haloalkylsulphonyloxy and X is chlorineor bromine.
 6. Compound of formula (Ib) according to claim 5, wherein R²is chlorine; R³ is methylsulphonyloxy and X is bromine.
 7. A productcomprising the compound of formula (Ia) according to claim 3 forproduction of one or more active fungicidal ingredients.
 8. A productcomprising the compound of formula (Ib) according to claim 5 forproduction of one or more active fungicidal ingredients.